Historically phosphate binders included aluminium salts. However, use of aluminium salts was found to result in toxic complications due to aluminium accumulation, e.g. reduction in haemoglobin production, impairment in natural repair and production of bone and possible impairment of neurological/cognitive function. Other aluminium compounds such as microcrystalline aluminium oxide hydroxide (boehmite) and certain hydrotalcites were proposed for this use, such as disclosed in Ookubo et al, Journal Pharmaceutical Sciences (November 1992), 81 (11), 1139-1140. However these suffer from the same drawbacks.
Calcium carbonate or calcium acetate are now typically used as phosphate binders. However these suffer from the drawback that they tend to promote hypercalcemia through the absorption of high amounts of ingested calcium and are linked to accelerated cardiovascular calcification which can cause serious side effects. Consequently, frequent monitoring of serum calcium levels is required during therapy with calcium-based phosphate binders. The National Kidney Foundation Kidney Disease Quality Outcomes Initiative suggests limiting the use of calcium based salts (Clinical Practice Guidelines for Bone Metabolism and Disease in Chronic Kidney Disease, Guide 5, pg 1 pt 5.5). Recent efforts, therefore, have focused on the development of phosphate binders free of calcium. More recently, lanthanum carbonate and sevelamer HCl have been used as calcium-free phosphate binders. Sevelamer hydrochloride is a water-absorbing, non-absorbed hydrogel-cross-linked polyallylamine hydrochloride but because of its structure also binds certain fat-soluble vitamins and bile acids and is therefore reported in V. Autissier et al, Journal of Pharmaceutical Sciences, Vol 96, No 10, October 2007 to require large doses to be effective because it has a higher propensity for the bound phosphate to be displaced by these competing anions. A high pill burden and/or large tablets are often associated with poor patient compliance and this type of product are also considered relatively expensive to their calcium counter parts. Sevelamer has also been associated with gastro intestinal (GI) adverse effects A. J. Hutchison et al, Drugs 2003; 63 (6), 577-596.
Lanthanum carbonate is a new phosphate binder which has been shown to be as effective as calcium carbonate with lower incidence of hypercalcaemia. Long-term administration of lanthanum, a rare earth element, continues to raise safety concerns with regards to the potential accumulation of a rare earth metal in body tissue which can be enhanced in renal failure—Tilman B Druke, Seminars in Dialysis, Volume 20, Issue 4 page 329-332 July/August 2007.
Many known inorganic preparations for treatment of hyperphosphataemia are efficient phosphate binders only over a limited pH range. Moreover, particularly alkaline binders could buffer the stomach pH up to a high level at which they would not have a phosphate binding capacity.
To overcome the drawbacks associated with aluminium and also problems of efficacy over a limited pH range, WO-A-99/15189 discloses use of mixed metal compounds which are free from aluminium and which have a phosphate binding capacity of at least 30% by weight of the total weight of phosphate present, over a pH range of from 2-8.
Typically, such mixed metal compounds may contain iron (III) and at least one of magnesium, calcium, lanthanum and cerium. Preferably they also contain at least one of hydroxyl and carbonate anions and optionally additionally, at least one of sulphate, nitrate, chloride and oxide. However, mixed metal compounds of WO-A-99/15189 may release some of their magnesium content in soluble form raising serum magnesium levels (Hypermagnesia).
PCT/GB2006/000452 discloses that the release of the divalent metal, e.g. magnesium, associated with the pharmaceutical use of compounds of WO-A-99/15189 can be significantly reduced by heat treatment of a suitable mixed metal compound, for example a layered double hydroxide or a compound having a hydrotalcite structure. However, the divalent metal although in a more acid resistant form than the untreated hydrotalcite structure still comprises sufficient quantities of the divalent metal form for these to be potentially released under extreme acid conditions such as those typically encountered in an empty stomach.
Seida et al (Water research 36 2002 1306-1312) discloses that phosphate binding by layered double hydroxides containing iron increases at a pH value maintained at pH 6.86 due to a combination of anion-exchange as well as precipitation or coagulation of the released divalent metal ion binding with phosphate. This compound was separated from the phosphate solution in order to determine the residual phosphate concentration in the solution. The isolated compound was not dried or milled and not intended for use as a new phosphate binder. Moreover the compound was already partially bound to phosphate thereby reducing remaining sites available for further phosphate binding. In addition, the teaching of Seida et al suggests that the presence of magnesium in the mixed metal compounds plays an important part in producing sufficient precipitation and increasing phosphate binding.
J. Das et al teaches that layered double hydroxides increasingly dissolve at pH values below 6 with a further decrease in phosphate binding. Ookubo et al (Langmuir 1993, 9, 1418-1422) teaches that layered double hydroxides (referred to as hydrotalcites) are soluble in strong acidic media and should only be used as drugs when the hydrotalcite is protected by an enteric acid resistant coating. However, enteric coated drugs would be acid resistant as well as being resistant to phosphate binding. Furthermore, Ookubo and Shin et al, Wat. Sci. Tech. 1996, Vol 34, No 1-2, page 161-168 teaches that the carbonate of hydrotalcite-type materials is not readily replaced by other anions and that chlorine comprising hydrotalcites should be used for binding phosphate.
J. Das et al, Applied Clay Science 32 2006 252-260 discloses magnesium aluminium mixed metal layered hydroxide compounds with a divalent:trivalent metal range of 2:1 to 4:1 wherein the phosphate binding decreases with increasing divalent:trivalent metal ratio. It is believed that the higher amount of the trivalent metal increases phosphate binding because it creates a higher net positive charge on the hydroxide layer compared to samples with less of the trivalent metal. However, the examples described in Das et al teach divalent:trivalent metal molar ratios not lower than 2:1. Moreover, Rives et al, Layered Double Hydroxides Present and Future, teaches that the preferred lower limit is 2:1 and not exceeding a ratio less than 1:1. Mg-depleted mixed metal compounds of divalent:trivalent ratios less than 2:1 were prepared in our laboratory either via modification of coprecipitation or precipitation methods described in WO-A-99/15189 by controlling the pH at a lower pH (i.e. pH value of 5) during the reaction-stage, which is in contrast to the teaching of WO-A-99/15189 describing an optimum pH range of 10-10.5. Alternatively, the mixed metal compounds of WO-A-99/15189 were treated after the precipitation reaction-stage (i.e. post-synthesis), with a depleting agent. Treatment of mixed metal compounds of WO-A-99/15189 containing carbonate anion with hydrochloric acid are preferred because they were found to result either in compounds with good phosphate binding but with lower release of the divalent cation and/or showed a decreased presence of a mixture of single metal compounds of MII(OH)2, MII(OH)3, un-reacted reagents or other non hydrotalcite crystalline phases. Furthermore, mixtures prepared by simply admixing two different single metal salts at equivalent ratio to the Mg-depleted compound were also found to have lower phosphate binding or more release of the divalent cation (Table 2).
Phosphate binders based on single metal types such iron-oxide-hydroxide FeOOH are disclosed in US617444 and EP1932808 or LaCarbonate disclosed in US2008/0187602 but require the presence of carbohydrate stabilisers to prevent time ageing and transformation into iron-oxides or La hydroxycarbonates during manufacture and typically have a lower phosphate binding capacity.
Thus there is an urgent and widespread need for a more effective phosphate binder which does not release trivalent or divalent ions into the blood stream, does not require enteric coating and which is effective over a wide pH range of from 2-8.
In one aspect the present invention provides a pharmaceutical composition comprising
(a) a mixed metal compound according to formula (I)MII1-aMIIIa  (I)wherein MII is at least one bivalent metal;MIII is at least one trivalent metal; and1>a>0.4;the compound contains at least one n-valent anion An− such that the compound is charge neutral; and(b) a pharmaceutically acceptable carrier, diluent, excipient or adjuvant.
It will be understood that
      a    =                  number        ⁢                                  ⁢        of        ⁢                                  ⁢        moles        ⁢                                  ⁢        of        ⁢                                  ⁢                  M          III                            (                              number            ⁢                                                  ⁢            of            ⁢                                                  ⁢            moles            ⁢                                                  ⁢            of            ⁢                                                  ⁢                          M              II                                +                      number            ⁢                                                  ⁢            of            ⁢                                                  ⁢            moles            ⁢                                                  ⁢            of            ⁢                                                  ⁢                          M              III                                      )              ;
In a further aspect the present invention provides a mixed metal compound for use as a medicament wherein the mixed metal compound is of formula (I)MII1-aMIIIa  (I)wherein MII is at least one bivalent metal;MIII is at least one trivalent metal; and1>a>0.4;the compound contains at least one n-valent anion An− such that the compound is charge neutral.
In a further aspect the present invention provides use of a mixed metal compound in the manufacture of a medicament for binding phosphate, wherein the mixed metal compound is of formula (I)MII1-aMIIIa  (I)wherein MII is at least one bivalent metal;
MIII is at least one trivalent metal; and
1>a>0.4;
the compound contains at least one n-valent anion An− such that the compound is charge neutral.
In a further aspect the present invention provides use of a mixed metal compound in the manufacture of a medicament for the prophylaxis or treatment of any one of hyperphosphataemia, renal insufficiency, hypoparathyroidism, pseudohypoparathyroidism, acute untreated acromegaly, chronic kidney disease (CKD), clinically significant change in bone mineralization (osteomalecia, adynamic bone disease, osteitis fibrosa), soft tissue calcification, cardiovascular disease associated with high phosphates, secondary hyperparathyroidism, over medication of phosphate salts and other conditions requiring control of phosphate absorption, wherein the mixed metal compound is of formula (I)MII1-aMIIIa  (I)wherein MII is at least one bivalent metal;MIII is at least one trivalent metal; and1>a>0.4;the compound contains at least one n-valent anion An− such that the compound is charge neutral.
In a further aspect the present invention provides a mixed metal compound of formula (IV)[MII1-aMIIIaOb(OH)d](An−)c.zH2O  (IV)wherein is at least one bivalent metal selected from Mg (II), Zn (II), Fe (II), Cu (II), Ca (II), La (II), Ce (II) and Ni (II);MIII is at least one trivalent metal selected from Mn(III), Fe(III), La(III) and Ce(III); andAn− is at least one n-valent anion and wherein at least one anion is carbonate;1>a>0.4;0≤b≤2the value of c for each anion is determined by the need for charge neutrality as expressed by the formula 2+a−2b−d−cn=0; and0≤d≤2.0<z≤5.
In a further aspect the present invention provides a mixed metal compound obtained by or obtainable by treatment with an acid, a chelating agent or a mixture thereof of a compound[MII1-aMIIIaOb(OH)d](An−)c.zH2O  (IV)wherein MII is at least one bivalent metal selected from Mg (II), Zn (II), Fe (II), Cu (II), Ca (II), La (II), Ce (II) and Ni(II);MIII is at least one trivalent metal selected from Mn(III), Fe(III), La(III) and Ce(III); andAn− is at least one n-valent anion and wherein at least one anion is carbonate;0<a≤0.4;0≤b≤2.the value of c for each anion is determined by the need for charge neutrality as expressed by the formula 2+a−2b−d−cn=0; and0≤d≤2.0<z≤5.
In a further aspect the present invention provides a process for the production of a magnesium-depleted mixed metal compound of formula (IV)[MII1-aMIIIaOb(OH)d](An−)c.zH2O  (IV)                wherein 1>a>0.4;the process comprising the steps of:        a) contacting a compound of formula (IV)[MII1-aMIIIaOb(OH)d](An−)c.zH2O  (IV)        wherein 0<a≤0.4;        with an acid, a chelating agent or a mixture thereof; and        b) optionally subjecting the resulting compound to heat treatment.wherein is at least one bivalent metal selected from Mg (II), Zn (II), Fe (II), Cu (II), Ca (II), La (II), Ce (II) and Ni(II);MIII is at least one trivalent metal selected from Mn(III), Fe(III), La(III) and Ce(III); andAn− is at least one n-valent anion and wherein at least one anion is carbonate;b 2.the value of c for each anion is determined by the need for charge neutrality as expressed by the formula 2+a−2b−d−cn=0; and0≤d≤2.0<z≤5.        
In a further aspect the present invention provides a pharmaceutical composition comprising
(a) a compound of the present invention or obtained/obtainable in accordance with the present invention, and
(b) a pharmaceutically acceptable carrier, diluent, excipient or adjuvant.
In a further aspect the present invention provides a compound of the present invention or obtained/obtainable in accordance with the present invention for use as a medicament.
In a further aspect the present invention provides use of a compound of the present invention or obtained/obtainable in accordance with the present invention in the manufacture of a medicament for binding phosphate.
In a further aspect the present invention provides use of a compound of the present invention or obtained/obtainable in accordance with the present invention in the manufacture of a medicament for the prophylaxis or treatment of any one of hyperphosphataemia, metabolic bone disease, metabolic syndrome, renal insufficiency, hypoparathyroidism, pseudohypoparathyroidism, acute untreated acromegaly, chronic kidney disease (CKD), clinically significant change in bone mineralisation (osteomalecia, adynamic bone disease, osteitis fibrosa), soft tissue calcification, cardiovascular disease associated with high phosphates, secondary hyperparathyroidism, over medication of phosphate salts and other conditions requiring control of phosphate absorption.
Furthermore the present invention provides a process for preparation of depleted compounds comprising oxide-hydroxide of metal having a M-O bond distance of approximately 2⊕ (angstrom) as determined by Extended X-Ray Absorption Fine Structure (EXAF) studies. More specifically, for depleted compound derived from a Mg Fe mixed metal compound (example A), the distance between the centre absorbing iron atom and its nearest oxygen atom neighbour is 1.994⊕ (1st shell distance). The distance between the centre absorbing iron atom and its nearest iron neighbour (M-O-M distance) is 3.045⊕ (2nd shell distance). A preferred range M-O bond distance is between 1.5-2.5⊕ and a preferred range of M-O-M distance is between 2-4⊕.
We have found surprisingly that under controlled conditions it is possible to remove the more soluble metal from the mixed metal compounds such as layered hydroxide structure or a heat-treated mixed metal compound whilst maintaining mixed metal compounds with divalent:trivalent molar ratios less than 1 with a typical hydrotalcite XRD signature, thereby creating metal-depleted mixed metal compounds with improved or maintained phosphate binding and a lower release of divalent or trivalent metal ions (such as magnesium) during the phosphate binding reaction. In addition or alternatively, the metal-depleted mixed metal compound may be heat-treated to increase phosphate-binding and reduce metal (e.g. magnesium) release further. The metal-depleted mixed metal compound has superior phosphate binding characteristics to the mixed metal compounds of WO-A-99/15189 and PCT/GB2006/000452. The metal-depleted mixed metal compound may be magnesium depleted. The magnesium-depleted mixed metal compound comprises a lower content of the more soluble divalent magnesium ion and more of the less soluble trivalent iron resulting in ratios of divalent Mg:trivalent Fe range significantly less than those previously reported for solid mixed metal compounds used for phosphate binding.
We have found that by using the carbonate instead of sulphate anion in the starting material, acidification of the mixed metal compound results in a cleaner compound i.e. with lower amounts of sulphates salts remaining in the depleted product; this is because of the acidification of the carbonate anion only leads to formation of water and carbon dioxide.
By mixed metal compound, it is meant that the atomic structure of the compound includes the cations of at least two different metals distributed uniformly throughout its structure. The term mixed metal compound does not include mixtures of crystals of two salts, where each crystal type only includes one metal cation. Mixed metal compounds are typically the result of coprecipitation from solution of different single metal compounds in contrast to a simple solid physical mixture of 2 different single metal salts. Mixed metal compounds as used herein include compounds of the same metal type but with the metal in two different valence states e.g. Fe(II) and Fe(III) as well as compounds containing more than 2 different metal types in one compound.
The mixed metal compound may also comprise amorphous (non-crystalline) material. By the term amorphous is meant either crystalline phases which have crystallite sizes below the detection limits of x-ray diffraction techniques, or crystalline phases which have some degree of ordering, but which do not exhibit a crystalline diffraction pattern and/or true amorphous materials which exhibit short range order, but no long-range order.
The substances of the invention may contain at least one compound of formula (I) or (IV). The process of preparing (such as) depleting the compound may also result in other materials being present in addition to compounds of formula (I) or (IV), for example single (as opposed to mixed) metal compounds may also be formed during the process.
The process for preparing compounds of formula (I) or (IV) may result in changes in the structure of the compound which is the starting material. Therefore the formula (I) or (IV) describe only the elemental composition of compounds of formula (I) or (IV) and do not provide a definition of structure
The compound of the present invention or for use in the present invention is preferably formed with no aging or hydrothermal treatment to avoid the crystals of the compound growing in size and to maintain a high surface area over which phosphate binding can take place. The compound of formula I is also preferably maintained in a fine particle size form during the post-synthesis route to maintain good phosphate binding. Preferably 90% of the compound of formula I based on volume (d90) has a particle size of less than 200 micron, more preferably 90% of the compound of formula I based on volume (d90) has a particle size of less than 100 micron, most preferably 90% of the compound of formula I based on volume (d90) has a particle size of less than 50 micron.
The compound of the present invention may also be prepared in the form of granulates. When comprised in the granulate form it is preferred that 90% of the compound of formula I based on volume (d90) has a particle size of less than 1000 micron, more preferably 90% of the compound of formula I based on volume (d90) has a particle size of less than 750 micron, most preferably 90% of the compound of formula I based on volume (d90) has a particle size of less than 500 micron even more preferred 90% of the compound of formula I based on volume (d90) has a particle size of less than 250 micron.
As used herein, the term “Layered Double Hydroxide” (LDH) is used to designate synthetic or natural lamellar hydroxides with two kinds of metallic cations in the main layers and interlayer domains containing anionic species. This wide family of compounds is sometimes also referred to as anionic clays, by comparison with the more usual cationic clays whose interlamellar domains contain cationic species. LDHs have also been reported as hydrotalcite-like compounds by reference to one of the polytypes of the corresponding [Mg—Al] based mineral. (See “Layered Double Hydroxides: Present and Future”, ed, V Rives, 2001 pub. Nova Science).
For ease of reference, these and further aspects of the present invention are now discussed under appropriate section headings. However, the teachings under each section are not necessarily limited to each particular section.